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Phytol Induces Apoptosis and ROS-Mediated Protective Autophagy in Human Gastric Adenocarcinoma AGS Cells

YeonWoo Song and Somi Kim Cho

Phytol, a diterpene alcohol produced from chlorophyll, is used widely as a food additive and an aromatic ingredient. However, the molecular mechanisms behind the cytotoxic effects of phytol in cancer cells are not understood. The current study demonstrated that phytol induces apoptosis in human gastric adenocarcinoma AGS cells, as evidenced by an increased cell population in the sub-G1 phase, downregulation of Bcl-2, upregulation of Bax, the activation of caspase-9 and -3, PARP cleavage, and depolarization of the mitochondrial membrane. In addition, phytol induced autophagy, as evidenced by the induction of acidic vesicle accumulation, the conversion of microtubule-associated protein LC3-I to LC3-II, and the suppression of Akt, mTOR, and p70S6K phosphorylation. Most importantly, pretreatment with chloroquine, a lysosomal inhibitor, strongly augmented phytol-induced apoptosis in AGS cells, suggesting that phytol could induce protective autophagy. Furthermore, co-treatment with a reactive oxygen species (ROS) scavenger enhanced the phytol-induced cytotoxicity, which is accompanied by the decrease in the levels of p62 as well as the percentage of acidic vesicular organelles (AVOs) positive cells, suggesting that the cytoprotective Nrf2 pathway was induced by phytol. Taken together, these findings provide valuable insights into the mechanisms by which phytol induces cell death in AGS cells.